Implication of European-derived adiposity loci in African Americans

Obesity is a major public health problem, resulting in increased morbidity and mortality and heavy economic burdens on health-care systems. In the United States, the financial consequence is considerable. A great deal of effort has been dedicated to research with the goal of understanding factors mediating disease risk and progression of obesity.;Obesity is a consequence of a greater intake of calories than the body requires. The prevalence of obesity and morbid obesity, defined as a BMI ≥30kg/m 2 and ≥40kg/m2, respectively, has seen a dramatic increase worldwide in the last few decades for both sexes and for all ages and ethnic groups. Risk for obesity is multifactorial and is therefore mediated by multiple factors including environmental surroundings, lifestyle, and genetics. The focus of this thesis is to investigate genetic mediators of obesity in African Americans by examining adiposity loci previously discovered in European-derived populations. Obesity affects ethnic groups at dissimilar rates and is more prevalent in African Americans than European Americans. Ethnicity is therefore an important factor to consider when researching this disease, and is one of the primary focal points of this work. Genetic factors may lead to the higher susceptibility of obesity in African Americans. Defining genes that affect obesity in African Americans may identify novel pathways for regulation of adiposity, which contributes strongly to many common diseases including type 2 diabetes, cardiovascular disease, and hypertension.;Within this thesis, over 50 novel European-derived adiposity loci, including 99 index variants, were assessed for association with body mass index in six African American cohorts. Subsequently, 50 exonic variants located in the coding regions of these same loci were investigated for BMI association in African Americans. The association of both index and exonic variants at these European-derived loci with additional measures of adiposity was also examined in African Americans. Finally, the role of coding and noncoding variants at the GALNT10 gene, a novel obesity risk locus identified in African-derived populations, was explored in African Americans.;The work presented here explores the differences in genetic variation in obesity between European- and African-derived populations, investigates whether novel or established variants modulate adiposity in African Americans, considers the implications of replication and lack of replication of these variants, and evaluates the impact this has on the genetics of this disease. This work broadens knowledge of the genetic components of this disease as well as confirms the necessity for further research to elucidate mechanisms influencing its risk and progression.